The aim of this research is to gain a better understanding of the mechanisms involved in the expression of dioxin induced toxicity. Our ongoing investigations use congenic haired and hairless HRS/J mice to study the regulatory mechanisms which control the expression of cutaneous toxicity following topical treatment with dioxin. The work in this proposal is based on the hypothesis that epidermal cells of haired as well as of hairless HRS/J mice have the potential to express dioxin induced hyperplasia and terminal differentiation (as demonstrated by in vitro studies), but that this response is inhibited in haired mice in vivo, while still being expressed in the hairless animals. Skin grafting experiments have demonstrated that this difference in response to dioxin is controlled at the cutaneous level, and is not dependent on circulatory factors. The present proposal outlines in vitro experiments which will examine the role of dermal cells in regulating the keratinocyte response to dioxin. In vivo and in vitro experiments will analyse the role of specific growth factors (EGF, TGFalpha, and TGFbeta) in mediating the effect of dioxin on murine skin in vivo, and on epidermal keratinocytes in vitro.